Pyrazole compounds and uses thereof

ABSTRACT

The present invention provides pyrazole derivatives of Formula (I), and in particular N1-(4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl) pyridin-2-yl)cyclohexane-1,4-diamine derivatives and related compounds as casein kinase 1 (CK1) and/or interleukin 1 receptor associated kinase 1 (IRAKI) inhibitors for treating cancer, inflammatory and immune related disorders.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a National Stage of International Application No.PCT/IL2018/050100, filed Jan. 30, 2018; which claims the benefit of thepriority of U.S. Provisional Application No. 62/453,192, filed Feb. 2,2017; the disclosure of each of which is incorporated herein byreference in its entirety.

TECHNOLOGICAL FIELD

The present invention provides pyrazole derivatives and uses thereof inmethods of treating malignant disease and disorders and methods fortreating inflammatory diseases and disorders.

BACKGROUND

The casein kinase 1 family (CK1 or CKI) are serine/threonine kinaseswith six members (isoforms) in humans: α, γ1, γ2, γ3, δ and ε. Theydiffer in length and sequence of the N-terminal (9-76 amino acids) andespecially the C-terminal (24-200 amino acids) non-catalytic domain(Schittek and Sinnberg, Mol. Cancer 2014, 13:231).

CK1δ and CK1ε are 98% identical in their kinase domain and 53% identicalin their C-terminal regulatory domain (Fish et al., J. Biol. Chem. 1995,270:14875-14883). Whereas, there is some redundancy with respect to CK1substrate phosphorylation, most CK1 isoforms have distinct biologicalroles. The wide range of CK1 substrates shows that the CK1 familymembers are involved in multiple cellular processes, from regulation ofmembrane trafficking, cytokinesis, vesicular transport, ribosomebiogenesis, DNA repair, signal transduction pathways, apoptosis and inthe circadian rhythm (Knippschild et al., Cell. Signal. 2005,17:675-689; Cheong and Virshup, Int. J. Biochem. Cell Biol. 2011,43:465-469; Zemp, et al., J. Cell Sci. 2014, 127:1242-1253).

CK1α plays a role in the mitotic spindle formation during cell divisionand in DNA repair mechanisms and participates in RNA metabolism(Knippschild et al., Cell Signal 2005, 17:675-689). It contributes tothe activation of mTOR via sustained degradation of the endogenous mTORinhibitor DEPTOR (Duan et al., Mol. Cell 2011, 44:317-324).

CK1α has a major role in regulation of the Wnt/β-catenin signalingpathway. The inventors of this application have shown that CK1α is a keycomponent of the β-catenin destruction complex. When the Wnt receptorsare not engaged, CK1α phosphorylates β-catenin at serine residue S45,which is necessary for the priming phosphorylation of another kinase,GSK3 (Amit et al., Genes Dev. 2002, 16:1066-1076).

β-catenin phosphorylation by GSK3 at residues T41, S37 and S33,generates an ubiquitination degron, recruiting the E3 SCF-β-TrCP,leading to the ubiquitination and degradation of β-catenin (Clevers andNusse, Cell 2012, 149:1192-1205). The inventors have further shown thatinducible ablation of CK1α in the mouse gut epithelium triggers amassive epithelial Wnt response, which surprisingly did not alterintestinal homeostasis, with only little enhanced proliferation and notumorigenesis (Elyada et al., Nature 2011, 470:409-413). This isdissimilar to the consequences of acute ablation of other components ofthe β-catenin destruction complex, such as APC, which results in loss ofhomeostasis and tumorigenesis (Sansom et al., Genes Dev. 2004,18:1385-1390).

The inventors of the present application have found that the reason forhomeostasis maintenance following CK1α ablation is that parallel to Wntactivation, CK1α ablation induces several tumor-suppressor pathways,among which are DNA damage response (DDR), cellular senescence and p53pathway activation (Elyada et al., Nature 2011, 470:409-413; Pribluda etal., Cancer Cell 2013, 24:1-5).

Whereas the molecular mechanisms underlying the activation of theseanti-neoplastic pathways are still elusive, the inventors have foundthat that CK1α ablation induces disproportionally minor DNA damage, withno signs of ATM activation, indicating that CK1α-induced DDR and p53activation likely entail uncommon molecular mechanisms (Burstain et al.,unpublished). In addition, the inventors have found that CK1α ablationresults in the induction of a new type of an inflammatory response,denoted parainflammation, which is confined to the epithelium, with nocommon signs of inflammatory response (inflammatory cell infiltration,calor, rubor, tumor, and dolor) (Pribluda et al., Cancer Cell 2013,24:1-5; Lasry and Ben-Neriah, Trends Immunol. 2015, 36:217-228).Parainflammation cooperates with WT p53 activation in suppressingtumorigenesis, yet switches to a tumor promoting mechanism in theabsence of functional p53 (Pribluda et al., Cancer Cell 2013, 24:1-5;Aran et al., Genome Biol. 2016, 17:145).

Whereas it is already established that CK1α is a major regulator of p53,the inventors have also found that the combined ablation of CK1δ andCK1ε in the gut epithelium also results in p53 activation, which maysynergize with CK1α-induced p53 activation.

IRAK1 was identified as a therapeutic target for MDS, and certainsubsets of AML and triple negative breast cancer (Rhyasen et al., CancerCell 2013, 24:90-104; Rhyasen et al., Exp. Hematol. 2013, 41:1005-7; Weeet al., Nat. Commun. 2015, 6:8746). IRAK1 mRNA is over-expressed in20-30% of MDS patients and the IRAK1 protein is dramaticallyover-expressed and is hyperactivated in a majority of MDS marrow sampleexamined. IRAK1 is a serine/threonine kinase that mediates signalselicited from Toll-like receptor (TLR) and Interleukin-1 Receptor(IL1R). Following receptor activation, IRAK1 becomes phosphorylatedwhich then leads to recruitment of TRAF6, resulting in TRAF6 activationof NF-κB and JNK pathways. The molecular source of IRAK1 overexpressionand/or hyperactivation in MDS (or AML) is not conclusive. It is thoughtthat over-expression of TLR or necessary cofactors in MDS clones mayresult in chronic IRAK1 activation even in the absence of infection.Small molecule inhibitors targeting IRAK1 (IRAK1/4 Inhibitor, AmgenInc.) have been originally developed for autoimmune and inflammatorydiseases. Given that IRAK1 is hyperactivated (i.e., phosphorylated) inMDS but not normal marrow cells, Starczynowski and colleagues showedthat IRAK-Inhibitor treatment (IRAK1/4, Amgen) and the knockdown ofIRAK1 resulted in dramatic impairment of MDS cell proliferation,progenitor function, and viability in vitro and in vivo. Yu andcolleagues showed that IRAK1 overexpression confers triple negativebreast cancer cells (TNBC) growth advantage through NF-κB-relatedcytokine secretion and metastatic TNBC cells exhibit gain of IRAK1dependency, resulting in high susceptibility to genetic andpharmacologic inhibition of IRAK1. Paclitaxel treatment of TNBC cellsinduces strong IRAK1 phosphorylation, an increase in inflammatorycytokine expression, enrichment of cancer stem cells and acquiredresistance to paclitaxel treatment. Pharmacologic inhibition of IRAK1was able to reverse paclitaxel resistance by triggering massiveapoptosis. IRAK1 was also found to be a DEK transcriptional target andis essential for head and neck cancer cell survival (Adams et al.,Oncotarget. 2015, 22; 6:43395-43407) and also as potential target in thetreatment of inflammatory- and immune-related disorders (Bahia et al.,Cell. Signal. 2015, 27:1039-55).

The inventors have thus found that compounds of the invention are ableto inhibit IRAK1, an important upstream regulator of the NF-kB pathway,which plays an important role in hematological malignancies.

GENERAL DESCRIPTION

The present invention provides a compound having Formula (I), or astereoisomer or salt thereof:

wherein:

R₁ and R₂ are each independently selected from H; and straight orbranched C₁-C₈ alkyl, straight or branched C₁-C₅ alkoxy, straight orbranched C₁-C₅ acyl, C₅-C₁₅ aryl, and C₃-C₇ heteroaryl, each optionallysubstituted by at least one of halide, hydroxyl, ester, ether, C₅-C₁₅aryl, C₃-C₇ heteroaryl, and amide; or

R₁ and R₂ together with the nitrogen atom they are connected to form a4-7 membered saturated, unsaturated, or aromatic ring that mayoptionally include at least one of N, O, NH, C═N, C═O, and SO₂, and canoptionally be substituted with at least one of straight or branchedC₁-C₅ alkyl, C₅-C₁₅ aryl, C₃-C₇ heteroaryl, hydroxyl, halide, and cyano;

R₃ and R₄ are each independently selected from H and straight orbranched C₁-C₈ alkyl optionally substituted by at least one of halide,hydroxyl, alkoxy, C₅-C₁₅ aryl, C₃-C₇ heteroaryl, ester, and amide; or

R₁ or R₂ together with R₃ and the carbon and nitrogen atoms they areeach connected to form a 4-7 membered saturated, unsaturated, oraromatic ring that may optionally include at least one of N, NH, O, C═N,C═O, and SO₂, and can optionally be substituted with at least one ofstraight or branched C₁-C₅ alkyl, C₅-C₁₅ aryl, C₃-C₇ heteroaryl,hydroxyl, carbonyl, and halide;

W, X, Y, and Z are each independently selected from CH, CR₅, CR_(5c),NH, N, and S; provided that at least one of W, X, Y and Z is selectedfrom NH, N and S; provided that, when W is N, Z is N, then X is CR_(5c);

n is an integer selected from 0 and 1;

R₅ is selected from OH, NH₂, and halide;

R_(5c) is selected from OH and NH₂;

R₈ is selected from H and halide; and straight or branched C₁-C₈ alkyl,straight or branched C₂-C₈ alkenyl, and straight or branched C₂-C₈alkynyl, each optionally substituted by at least one halide;

R₆ is selected from straight or branched C₁-C₈ alkyl, straight orbranched C₂-C₈ alkenyl, straight or branched C₂-C₈ alkynyl, C₅-C₁₀cycloalkyl, and saturated or unsaturated 4-6 membered heterocyclyle;each optionally substituted by at least one of straight or branchedC₁-C₈ alkyl, C₃-C₇ cycloalkyl, 4-6 membered heterocyclyle, C₅-C₁₅ aryl,C₃-C₇ heteroaryl, halide, hydroxyl, and C₁-C₅ alkyl halide; and

R₇ is selected from straight or branched C₁-C₈ alkyl, straight orbranched C₂-C₈ alkenyl, and straight or branched C₂-C₈ alkynyl; eachindependently substituted by at least one of C₃-C₇ cycloalkyl, 4-6membered heterocyclyle, C₅-C₁₅ aryl, C₃-C₇ heteroaryl, halide, hydroxyl,and C₁-C₅ alkyl halide.

The present invention provides a compound having Formula (I), or astereoisomer or salt thereof:

wherein:

R₁ and R₂ are each independently selected from H; and straight orbranched C₁-C₈ alkyl, straight or branched C₁-C₅ alkoxy, straight orbranched C₁-C₅ acyl, C₅-C₁₅ aryl, and C₃-C₇ heteroaryl, each optionallysubstituted by at least one of halide, hydroxyl, ester, ether, C₅-C₁₅aryl, C₃-C₇ heteroaryl, and amide; or

R₁ and R₂ together with the nitrogen atom they are connected to form a4-7 membered saturated, unsaturated, or aromatic ring that mayoptionally include at least one of N, O, NH, C═N, C═O, and SO₂, and canoptionally be substituted with at least one of straight or branchedC₁-C₅ alkyl, C₅-C₁₅ aryl, C₃-C₇ heteroaryl, hydroxyl, halide, and cyano;

R₃ and R₄ are each independently selected from H and straight orbranched C₁-C₈ alkyl optionally substituted by at least one of halide,hydroxyl, alkoxy, C₅-C₁₅ aryl, C₃-C₇ heteroaryl, ester, and amide; or

R₁ or R₂ together with R₃ and the carbon and nitrogen atoms they areeach connected to form a 4-7 membered saturated, unsaturated, oraromatic ring that may optionally include at least one of N, NH, O, C═N,C═O, and SO₂, and can optionally be substituted with at least one ofstraight or branched C₁-C₅ alkyl, C₅-C₁₅ aryl, C₃-C₇ heteroaryl,hydroxyl, carbonyl, and halide;

W, X, Y, and Z are each selected from CH, CR₅, NH, N, and S; providedthat at least one of W, X, Y, and Z is selected from NH, N and S;provided that, when W is N and Z is N, then R₈ is other than H;

n is an integer selected from 0 and 1;

R₅ is selected from OH, NH₂, and halide;

R₈ is selected from H and halide; and straight or branched C₁-C₈ alkyl,straight or branched C₂-C₈ alkenyl, and straight or branched C₂-C₈alkynyl, each optionally substituted by at least one halide;

R₆ is selected from straight or branched C₁-C₈ alkyl, straight orbranched C₂-C₈ alkenyl, straight or branched C₂-C₈ alkynyl, C₅-C₁₀cycloalkyl, and saturated or unsaturated 4-6 membered heterocyclyle;each optionally substituted by at least one of straight or branchedC₁-C₈ alkyl, C₃-C₇ cycloalkyl, 4-6 membered heterocyclyle, C₅-C₁₅ aryl,C₃-C₇ heteroaryl, halide, hydroxyl, and C₁-C₅ alkyl halide; and

R₇ is selected from straight or branched C₁-C₈ alkyl, straight orbranched C₂-C₈ alkenyl, and straight or branched C₂-C₈ alkynyl, eachindependently substituted by at least one of C₃-C₇ cycloalkyl, 4-6membered heterocyclyle, C₅-C₁₅ aryl, C₃-C₇ heteroaryl, halide, hydroxyl,and C₁-C₅ alkyl halide.

In some embodiments, R₁ and R₂ are each independently selected from H,and straight or branched C₁-C₈ alkyl optionally substituted by at leastone of halide, C₅-C₁₅ aryl, C₃-C₇ heteroaryl, hydroxyl, ester, ether,and amide.

In other embodiments, R₁ and R₂ are each independently selected from H,and straight or branched C₁-C₅ alkoxy optionally substituted by at leastone of halide, hydroxyl, ester, and amide.

In further embodiments, R₁ and R₂ are each independently selected fromH, and C₁-C₅ acyl optionally substituted by at least one of halide,hydroxyl, ester, ether, and amide.

In some other embodiments, R₁ and R₂ are each independently selectedfrom H and C₅-C₁₅ aryl optionally substituted by at least one of halide,hydroxyl, ester, ether, and amide.

In some embodiments, R₄ is H. In other embodiments, R₃ and R₄ are H.

In other embodiments, R₅ is halide. In some embodiments, R₅ is NH₂. Insome embodiments, R₅ is OH.

In other embodiments, R₈ is selected from H, C₁, and straight orbranched C₁-C₄ alkyl. In other embodiments, R₈ is H.

In some embodiments, at least one of R₁ and R₂ is H.

In some embodiments, R₆ selected from straight or branched C₁-C₈ alkyl,C₅-C₁₀ cycloalkyl, and saturated or unsaturated 4-6 memberedheterocyclyle; and R₇ is selected from straight or branched C₁-C₈ alkyl,substituted by at least one of C₃-C₇ cycloalkyl, 4-6 memberedheterocyclyle, C₅-C₁₅ aryl, C₃-C₇ heteroaryl, halide, hydroxyl, andC₁-C₅ alkyl halide.

In some embodiments, R₆ is selected from straight or branched C₁-C₈alkyl, C₅-C₁₀ cycloalkyl, and 4-6 membered saturated heterocyclyle.

In other embodiments, R₇ is straight or branched C₁-C₈ alkyl substitutedby at least one of C₃-C₇ cycloalkyl and hydroxyl.

In some embodiments, R₆ is selected from straight or branched C₁-C₈alkyl, and saturated, unsaturated, or aromatic 4-6 memberedheterocyclyle, each optionally substituted by at least one of straightor branched C₁-C₈ alkyl, C₃-C₇ cycloalkyl, halide, hydroxyl, and CF₃.

In some embodiments, R₇ is straight or branched C₁-C₈ alkyl substitutedby at least one C₃-C₇ cycloalkyl.

In other embodiments, R₁ and R₂ together with the nitrogen atom they areconnected to form a 4-7 membered saturated ring optionally including atleast one of N, O, NH, C═N, C═O, and SO₂, and can optionally besubstituted with at least one of straight or branched C₁-C₅ alkyl,hydroxyl, halide, and cyano.

In some embodiments, R₁ and R₂ together with the nitrogen atom they areconnected to form a 4-7 membered saturated ring.

In some embodiments, R₁ and R₂ together with the nitrogen atom they areconnected to form a 4-7 membered saturated ring including at least oneof N and O.

In further embodiments, R₁ and R₂ together with the nitrogen atom theyare connected to form a 4-7 membered aromatic ring optionally includingat least one of N and O.

In other embodiments, R₃ and R₄ are H.

In some embodiments, R₁ or R₂ together with R₃ and the carbon andnitrogen atom they are connected to form a 4-7 membered saturated ringthat optionally includes at least one of N, NH, O, C═O, and SO₂, and canoptionally be substituted with at least one of straight or branchedC₁-C₅ alkyl, hydroxyl, carbonyl, and halide.

In some embodiments, R₁ or R₂ together with R₃ and the carbon andnitrogen atom they are connected to form a 4-7 membered saturated ringthat includes at least one of NH, O, and C═O.

In other embodiments, n is 1. When n is 1, the ring it relates to is asix membered heteroaromatic ring. In further embodiments, n is 0. When nis 0, the ring it relates to is a five membered heteroaromatic ring.Under this embodiment, when n is 0 and Y is therefore absent, X will bedirectly connected to the carbon atom on one side and to W on the otherside.

In some embodiments, one of W, X, Y and Z is N. In further embodiments,two of W, X, Y and Z is N. In other embodiments, two of W, X, Y and Zare independently selected from NH, N, and S. In some embodiments, X isselected from CH, CR₅, and CR_(5c). In some embodiments, W is N, Z is N,and X is CR_(5c).

In some embodiments, a compounds of the invention is selected from thefollowing, wherein R₁-R₈ are as defined herein above:

In some embodiments, a compound of the invention is selected from thefollowing:

The term “straight or branched C₁-C₈ alkyl” should be understood toencompass a hydrocarbon saturated chain, which can be straight orbranched, comprising 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms.

The term “straight or branched C₂-C₈ alkenyl” or “straight or branchedC₂-C₅ alkenyl” should be understood to encompass a hydrocarbon chainhaving at least one double bond between any two adjacent carbon atoms inthe chain, which can be straight or branched, comprising 2, 3, 4, 5, 6,7, or 8 carbon atoms or 2, 3, 4, 5 carbon atoms, respectively.

The term “straight or branched C₂-C₈ alkynyl” should be understood toencompass a hydrocarbon chain having at least one triple bond betweenany two adjacent carbon atoms in the chain, which can be straight orbranched, comprising 2, 3, 4, 5, 6, 7, or 8 carbon atoms.

The term “straight or branched C₁-C₅ alkoxy” should be understood toencompass an —OR₉ moiety wherein R₉ is straight or branched C₁-C₅ alkyl.

The term “halide” should be understood to encompass any halogen radicalselected from F, —Br, —Cl, and —I.

The term “C₁-C₅ alkyl halide” should be understood to encompass anystraight or branched alkyl chain having between 1 to 5 carbon atomsbeing substituted by at least one halogen radical selected from F, —Br,—Cl, and —I, at any point one the straight or branched chain. In someembodiments, alkyl halide includes one halogen; in other embodiments,alkyl halide includes two halogen atoms (the same or different); inother embodiments, alkyl halide includes three halogen atoms (the sameor different).

The term “hydroxyl” should be understood to encompass OH.

The term “ester” should be understood to encompass any of C(═O)OR₁₀ or—OC(═O)R₁₀, wherein R₁₀ is straight or branched C₁-C₈ alkyl.

The term “amide” should be understood to encompass any of C(═O)NR₁₁R₁₂′,—NR₁₁C(═O)R₁₂′, wherein R₁₁ and R₁₂′ are each independently H, orstraight or branched C₁-C₈ alkyl.

The term “ether” should be understood to encompass any of R₁₃OR₁₄′ orOR₁₅′, wherein R₁₃ is selected from straight or branched C₁-C₈ alkylene,and R₁₄′ and R₁₅′ are each independently selected from straight orbranched C₁-C₈ alkyl.

The term “straight or branched C₁-C₅ acyl” should be understood toencompass any C(═O)R₁₆, wherein R₁₆ is C₁-C₅ straight or branched alkyl.

The term “C₅-C₁₅ aryl” should be understood to encompass any single orfused aromatic ring system comprising 5 to 7 carbon atoms. Examplesinclude, but are not limited to, phenyl, pentalenyl, naphtalenyl, andanthracenyl.

The term “C₃-C₇ heteroaryl” should be understood to encompass any singleor fused aromatic ring system comprising 3 to 7 carbon atoms and atleast one heteroatom selected from N, O, and S. Examples include, butare not limited to, furanyl, benzofuranyl, isobenzofuranyl, pyrrolynyl,indolynyl, isoindolinyl, thiophenyl, banzothiophenyl,banzo[c]thiophenyl, imidazolyl, benzimidazolyl, purinyl, pyrazolyl,indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl,thiasolyl, benzothiazolyl, pyridinyl, auinolinyl, isoquinolinyl,pyromodinyl, quinzolinyl, pyridazinyl, and cinnolinyl.

When referring to the embodiment wherein R₁ and R₂ together with thenitrogen atom they are connected to form a 4-7 membered saturated,unsaturated, or aromatic ring, it should be understood to relate to anyring that may be formed having 4, 5, 6, or 7 members including saidnitrogen atom. Said ring can be saturated, i.e., having all sigma bonds,unsaturated, i.e., having at least one double or at least one triplebond or any combinations thereof or aromatic, i.e., a ring system thatpossess aromatic character, cyclically conjugated molecular ring systemwith a stability (due to delocalization) significantly greater than thatof a hypothetical localized structure (e.g., Kekulé structure).

For example, said ring can be selected from piperidinyl, pyrrolidinyl,and azetidinyl.

When referring to the embodiments wherein R₁ or R₂ together with R₃ andthe carbon and nitrogen atom they are connected to form a 4-7 memberedsaturated, unsaturated or aromatic ring, it should be understood torelate to any ring that may be formed having 4, 5, 6, or 7 membersincluding said nitrogen atom. This ring forms a spiro bi-ring systemwith the cyclohexyl ring in the backbone of compound of formula I. Saidring can be saturated, i.e., having all sigma bonds, or unsaturated,i.e., having at least one double or at least one triple bond or anycombinations thereof. In some embodiments, the ring is an aromatic ring.

The term “C₃Cm cycloalkyl” or the term “C₃-C₇ cycloalkyl” should beunderstood to encompass a saturated (i.e., the ring containing onlysigma bonds between its members) hydrocarbon ring that comprises 5, 6,7, 8, 9, or 10 carbon atoms or 3, 4, 5, 6, or 7 carbon atoms,respectively.

The term “saturated, unsaturated or aromatic 4-6 membered heterocyclyle”should be understood to encompass a saturated (i.e., the ring containingonly sigma bonds between its members), unsaturated or aromatic (i.e.,the ring containing at least one double bond or at least one triple bondor any combinations thereof) ring containing 4, 5, or 6 members at leastone of which is a heteroatom selected from N, O, S, and P.

The term “optionally substituted” as used herein means that the groupsin question are either unsubstituted or substituted with one or more ofthe substituents specified. When the groups in question are substitutedwith more than one substituent, the substituents may be the same ordifferent.

Certain of the compounds described herein may contain one or more chiralcenter, or may otherwise be capable of existing as two enantiomers orseveral diastereomers. Accordingly, the compounds of this inventioninclude also mixtures of enantiomers as well as purified enantiomers orenantiomerically enriched mixtures. The compounds of this inventioninclude also mixtures of diastereomers, as well as purifieddiastereomers or diastereomerically enriched mixtures.

The invention also includes any salt of a compound of formula (I),including any pharmaceutically acceptable salt, wherein a compound ofthe invention has a net charge (either positive or negative) and atleast one counter ion (having a counter negative or positive charge) isadded thereto to form said salt. The phrase “pharmaceutically acceptablesalt(s)” as used herein means those salts of compounds of the inventionthat are safe and effective for pharmaceutical use in mammals and thatpossess the desired biological activity. Pharmaceutically acceptablesalts include salts of acidic or basic groups present in compounds ofthe invention. Pharmaceutically acceptable acid addition salts include,but are not limited to, hydrochloride, hydrobromide, hydroiodide,nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate,acetate, lactate, salicylate, citrate, tartrate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucaronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonateand pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.Certain compounds of the invention can form pharmaceutically acceptablesalts with various amino acids. Suitable base salts include, but are notlimited to, aluminum, calcium, lithium, magnesium, potassium, sodium,zinc, and diethanolamine salts. For a review on pharmaceuticallyacceptable salts, see Berge et al., J. Pharm. Soc. 1977, 66:1-19,incorporated herein by reference.

In some embodiments, the compound is a hydrochloride salt. In otherembodiments, the compound is a monohydrochloride salt. In otherembodiments, is a dihydrochloride salt.

The invention further provides a composition comprising at least onecompound as defined in any one of the embodiments herein above.

The present invention also relates to pharmaceutical compositionscomprising a compound of the subject invention in admixture withpharmaceutically acceptable auxiliaries, and optionally othertherapeutic agents. The auxiliaries must be “acceptable” in the sense ofbeing compatible with the other ingredients of the composition and notdeleterious to the recipients thereof.

Pharmaceutical compositions include those suitable for oral, rectal,nasal, topical (including transdermal, buccal and sublingual), vaginalor parenteral (including subcutaneous, intramuscular, intravenous andintradermal) administration or administration via an implant. Thecompositions may be prepared by any method well known in the art ofpharmacy.

Such methods include the step of bringing in association compounds ofthe invention or combinations thereof with any auxiliary agent. Theauxiliary agent(s), also named accessory ingredient(s), include thoseconventional in the art, such as carriers, fillers, binders, diluents,disintegrants, lubricants, colorants, flavouring agents, anti-oxidants,and wetting agents.

Pharmaceutical compositions suitable for oral administration may bepresented as discrete dosage units such as pills, tablets, drageés orcapsules, or as a powder or granules, or as a solution or suspension.The active ingredient may also be presented as a bolus or paste. Thecompositions can further be processed into a suppository or enema forrectal administration.

The invention further includes a pharmaceutical composition, ashereinbefore described, in combination with packaging material,including instructions for the use of the composition for a use ashereinbefore described.

For parenteral administration, suitable compositions include aqueous andnon-aqueous sterile injection. The compositions may be presented inunit-dose or multi-dose containers, for example sealed vials andampoules, and may be stored in a freeze-dried (lyophilised) conditionrequiring only the addition of sterile liquid carrier, for examplewater, prior to use. For transdermal administration, e.g., gels, patchesor sprays can be contemplated. Compositions or formulations suitable forpulmonary administration e.g. by nasal inhalation include fine dusts ormists which may be generated by means of metered dose pressurizedaerosols, nebulisers or insufflators.

The exact dose and regimen of administration of the composition willnecessarily be dependent upon the therapeutic or nutritional effect tobe achieved and may vary with the particular formula, the route ofadministration, and the age and condition of the individual subject towhom the composition is to be administered.

The term “treatment” or “therapy” as used herein means the managementand care of a patient for the purpose of combating a disease, disorderor condition. The term is intended to include the delaying of theprogression of the disease, disorder or condition, the alleviation orrelief of symptoms and complications, and/or the cure or elimination ofthe disease, disorder or condition. The patient to be treated ispreferably a mammal, in particular a human being.

It should be understood that the dosage ranges set forth above areexemplary only and are not intended to limit the scope of thisinvention. The therapeutically effective amount for each active compoundcan vary with factors including but not limited to the activity of thecompound used, stability of the active compound in the patient's body,the severity of the conditions to be alleviated, the total weight of thepatient treated, the route of administration, the ease of absorption,distribution, and excretion of the active compound by the body, the ageand sensitivity of the patient to be treated, and the like, as will beapparent to a skilled artisan. The amount of administration can beadjusted as the various factors change over time.

For oral delivery, the active compounds can be incorporated into aformulation that includes pharmaceutically acceptable carriers such asbinders (e.g., gelatin, cellulose, gum tragacanth), excipients (e.g.,starch, lactose), lubricants (e.g., magnesium stearate, silicondioxide), disintegrating agents (e.g., alginate, Primogel, and cornstarch), and sweetening or flavoring agents (e.g., glucose, sucrose,saccharin, methyl salicylate, and peppermint). The formulation can beorally delivered in the form of enclosed gelatin capsules or compressedtablets. Capsules and tablets can be prepared in any conventionaltechniques. The capsules and tablets can also be coated with variouscoatings known in the art to modify the flavors, tastes, colors, andshapes of the capsules and tablets. In addition, liquid carriers such asfatty oil can also be included in capsules.

Suitable oral formulations can also be in the form of suspension, syrup,chewing gum, wafer, elixir, and the like. If desired, conventionalagents for modifying flavors, tastes, colors, and shapes of the specialforms can also be included. In addition, for convenient administrationby enteral feeding tube in patients unable to swallow, the activecompounds can be dissolved in an acceptable lipophilic vegetable oilvehicle such as olive oil, corn oil and safflower oil.

The active compounds can also be administered parenterally in the formof solution or suspension, or in lyophilized form capable of conversioninto a solution or suspension form before use. In such formulations,diluents or pharmaceutically acceptable carriers such as sterile waterand physiological saline buffer can be used. Other conventionalsolvents, pH buffers, stabilizers, anti-bacteria agents, surfactants,and antioxidants can all be included. For example, useful componentsinclude sodium chloride, acetates, citrates or phosphates buffers,glycerin, dextrose, fixed oils, methyl parabens, polyethylene glycol,propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid, andthe like. The parenteral formulations can be stored in any conventionalcontainers such as vials and ampoules.

Routes of topical administration include nasal, bucal, mucosal, rectal,or vaginal applications. For topical administration, the activecompounds can be formulated into lotions, creams, ointments, gels,powders, pastes, sprays, suspensions, drops and aerosols. Thus, one ormore thickening agents, humectants, and stabilizing agents can beincluded in the formulations. Examples of such agents include, but arenot limited to, polyethylene glycol, sorbitol, xanthan gum, petrolatum,beeswax, or mineral oil, lanolin, squalene, and the like. A special formof topical administration is delivery by a transdermal patch. Methodsfor preparing transdermal patches are disclosed, e.g., in Brown, et al.,Ann. Rev. Med. 1988, 39:221-229, which is incorporated herein byreference.

Subcutaneous implantation for sustained release of the active compoundsmay also be a suitable route of administration. This entails surgicalprocedures for implanting an active compound in any suitable formulationinto a subcutaneous space, e.g., beneath the anterior abdominal wall.See, e.g., Wilson et al., J. Clin. Psych. 1984, 45:242-247. Hydrogelscan be used as a carrier for the sustained release of the activecompounds. Hydrogels are generally known in the art. They are typicallymade by crosslinking high molecular weight biocompatible polymers into anetwork, which swells in water to form a gel like material. In someinstances, hydrogels are biodegradable or biosorbable. For purposes ofthis invention, hydrogels made of polyethylene glycols, collagen, orpoly(glycolic-co-L-lactic acid) may be useful. See, e.g., Phillips etal., J. Pharmaceut. Sci. 1984, 73:1718-1720.

The invention further provides a compound as defined in any one of theembodiments herein above for use in therapy. The invention furtherprovides a compound as defined in any one of the embodiments hereinabove for use as a medicament.

The invention provides a compound as defined in any one of theembodiments herein above, for use in the inhibition of and least one ofCasein kinase I (CKI) and Interleukin-1 receptor-associated kinase 1(IRAK1).

The invention provides a compound as defined in any one of theembodiments herein above, for use in the inhibition of Casein kinase I(CKI).

The invention provides a compound as defined in any one of theembodiments herein above, for use in the inhibition of Interleukin-1receptor-associated kinase 1 (IRAK1).

The invention provides a compound as defined in any one of theembodiments herein above, for use in inducing anti-tumor response. Insome embodiments, said anti-tumor response comprises cancerimmunotherapy response.

The invention provides a compound as defined in any one of theembodiments herein above, for use in the treatment of a condition,symptom or disease associated with a malignant condition.

In some embodiments, said malignant condition is cancer. In otherembodiments, malignant condition is selected from hematologicalmalignancies, multiple myeloma, myelodysplastic syndrome (MDS), acutemyeloid leukemia (AML), melanoma, ER-negative breast cancer, diffuselarge B cell lymphoma (DLBCL), chronic myelogenous leukemia (CML),chronic lymphocytic leukemia (CLL), and head and neck cancer.

In some embodiments, said cancer has WT p53.

The invention provides a compound as defined in any one of theembodiments herein above, for use in the treatment of cancer having WTp53, wherein said WT p53 is a biomarker for the said compound efficacy.In some embodiments, said cancer is selected from Multiple myeloma,leukemia, malignant melanoma, breast cancer, prostate cancer, colorectalcancer and any combinations thereof.

The invention further provides a compound as defined in any one of theembodiments herein above, for use in the induction of cancerimmunotherapy response.

The invention provides a compound as defined in any one of theembodiments herein above, for use in the treatment of an inflammatoryand immune related disorder including a condition, symptom or diseaseassociated therewith.

The invention provides a method of inhibiting at least one of Caseinkinase I (CKI) and Interleukin-1 receptor-associated kinase 1 (IRAK1) ina subject in need thereof comprising the step of administrating to saidsubject at least one compound as defined in any one of the embodimentsherein above.

The invention further provides a method of inhibiting casein kinase I(CKI) in a subject in need thereof comprising the step of administratingto said subject at least one compound as defined in any one of theembodiments herein above.

The invention provides a method of inhibiting interleukin-1receptor-associated kinase 1 (IRAK1) in a subject in need thereofcomprising the step of administrating to said subject at least onecompound as defined in any one of the embodiments herein above.

The invention further provides a method for inducing an immunotherapyresponse in a subject in need thereof, said method comprising the stepof administering to said subject at least one compound as defined in anyone of the embodiments herein above.

The invention further provides a method of treating an inflammatory andimmune related disorder, including a condition, symptom or diseaseassociated therewith in a subject in need thereof, said methodcomprising the step of administering to said subject at least onecompound as defined in any one of the embodiments herein above.

The term “Casein kinase I” should be understood to encompass a proteinkinases family that are serine/threonine-selective enzymes that functionas regulators of signal transduction pathways in most eukaryotic celltypes. CK1 isoforms are involved in Wnt signaling, circadian rhythms,nucleo-cytoplasmic shuttling of transcription factors, DNA repair, p53activation and DNA transcription.

The term “Interleukin-1 receptor-associated kinase 1” should beunderstood to encompass an enzyme encoded by the IRAK1 gene which wasfound to be an important upstream regulator of the NF-kB pathwayinvolved in disease pathways of hematological malignancies, such asmultiple myeloma, MDS, leukemia and lymphoma, breast cancer, head andneck cancer, inflammatory and immune related disorders and others.

When referring to the “inhibition” of said enzyme, it should beunderstood to encompass any qualitative or quantitative decrease in theactivity of said enzyme due to direct or indirect binding of at leastone compound of the invention to said enzyme.

The term “induced anti-tumor response” should be understood to encompassany qualitative or quantitative chemotherapy of cancerous tumors.

The term “cancer immunotherapy response” should be understood toencompass any qualitative or quantitative cancer immunotherapy inductionof the subject's own immune system to fight the cancerous cells.Typically, immunotherapies can be categorized as active, passive orhybrid (active and passive), and are designed to exploit the fact thatcancer cells often have molecules on their surface that can be detectedby the immune system of a subject, known as tumour-associated antigens(TAAs); they are often proteins or other macromolecules (e.g.,carbohydrates). Active immunotherapy directs the immune system to attacktumor cells by targeting TAAs. Passive immunotherapies enhance existinganti-tumor responses.

When referring to “inflammatory and immune related disorders” it shouldbe understood to relate to any type of disorder (including conditions,symptoms and diseases associated therewith) that are treatable withInterleukin-1 receptor associated kinase inhibitors. It has been shownfor example that IRAK1 is an indispensable element of IL-Rs and TLRpathways that can regulate the abnormal levels of cytokines, andtherefore can be employed to manage immune- and inflammation-relateddisorders such as for example rheumatoid arthritis, inflammatory boweldisease, psoriasis, gout, asthma and cancer (Bahia et al., Cell. Signal.2015, 27:1039-55).

BRIEF DESCRIPTION OF THE DRAWINGS

In order to better understand the subject matter that is disclosedherein and to exemplify how it may be carried out in practice,embodiments will now be described, by way of non-limiting example only,with reference to the accompanying drawings, in which:

FIG. 1 shows the dose-response analysis in RKO cells. RKO cells wereincubated for 16 hours at 37° C. with indicated concentrations of thecompounds, or with the vehicle (DMSO) alone (−) and analyzed by WesternBlot. Shown are Western Blot signals of β-catenin and p53 stabilizationand phosphorylation of H2AX (γH2AX), a marker of DNA damage.

DETAILED DESCRIPTION OF EMBODIMENTS

The invention further provides a compound of Formula I′:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein:

R₁ and R₂ are each independently H, deuterium, C₁-C₈ alkyl, C₂-C₈alkenyl, C₁-C₈ alkynyl, C₃-C₁₀ cycloalkyl, C₆-C₁₅ aryl, C₇-C₁₆ aralkyl,heteroaryl, heterocyclyl, —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R_(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); or R₁ and R₂ together withthe nitrogen atom to which they are connected form heteroaryl orheterocyclyl;

R₃ and R₄ are each independently H, deuterium, halo, cyano, nitro, C₁-C₈alkyl, C₂-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₁₀ cycloalkyl, C₆-C₁₅ aryl,C₇-C₁₆ aralkyl, heteroaryl, or heterocyclyl; or R₁ and R₃ together withthe carbon and nitrogen atoms to which they are connected formheterocyclyl;

W, X, Y, and Z are each independently CR_(5a) or N, provided that, whenW and Z are each N, at least one of X and Y is N; or

W, X, and Z are each independently CR_(5a), NR_(5b), N, O, or S; and Yis a bond;

each R_(5a) is independently H, deuterium, halo, cyano, nitro, C₁-C₈alkyl, C₂-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₁₀ cycloalkyl, C₆-C₁₅ aryl,C₇-C₁₆ aralkyl, heteroaryl, heterocyclyl, —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), (NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), S(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c) or —S(O)₂NR^(1b)R^(1c);

each R_(5b) is independently H, deuterium, C₁-C₈ alkyl, C₂-C₈ alkenyl,C₁-C₈ alkynyl, C₃-C₁₀ cycloalkyl, C₆-C₁₅ aryl, heteroaryl, heterocyclyl,—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —S(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

R₆ is H, deuterium, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₁₀cycloalkyl, C₆-C₁₅ aryl, heteroaryl, heterocyclyl, —C(O)R^(1a),—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c) or —S(O)₂NR^(1b)R^(1c);

R₇ and R₈ are each independently H, deuterium, halo, cyano, nitro, C₁-C₈alkyl, C₂-C₈ alkenyl, C₁-C₈ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkyl-C₁-C₈ alkyl, C₆-C₁₅ aryl, C₇-C₁₆ aralkyl, heteroaryl,heterocyclyl, —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); and

each R^(1a), R^(1b), R^(1c), and R^(1d) is independently H, deuterium,C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₀ cycloalkyl, C₆-C₁₅aryl, C₇-C₁₆ aralkyl, heteroaryl, or heterocyclyl; or R^(1a) and R^(1c)together with the C and N atoms to which they are attached formheterocyclyl;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl,heteroaryl, and heterocyclyl is optionally substituted with one or moresubstituents Q, where each Q is independently selected from (a)deuterium, cyano, halo, and nitro; (b) C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, C₃-C₁₀ cycloalkyl, C₆-C₁₅ aryl, C₇-C₁₆ aralkyl, heteroaryl, andheterocyclyl, each of which is further optionally substituted with oneor more, in one embodiment, one, two, three, or four, substituentsQ^(a); and (c) —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),—C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a),—OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a),—OS(O)NR^(b)R^(c), —OS(O)₂NR^(a)R^(c), —NR^(a)R^(c), —NR^(a)C(O)R^(d),—NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c),—NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c),—NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b),R^(c), and R^(d) is independently (i) hydrogen or deuterium; (ii) C₁-C₈alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₀ cycloalkyl, C₆-C₁₅ aryl,C₇-C₁₆ aralkyl, heteroaryl, or heterocyclyl, each optionally substitutedwith one or more, in one embodiment, one, two, three, or four,substituents Q^(a); or (iii) R^(b) and R together with the N atom towhich they are attached form heterocyclyl, optionally substituted withone or more, in one embodiment, one, two, three, or four, substituentsQ^(a);

wherein each Q^(a) is independently selected from the group consistingof (a) deuterium, cyano, halo, and nitro; (b) C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₁₀ cycloalkyl, C₆—C₁₅ aryl, C₇-C₁₆ aralkyl,heteroaryl, and heterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e),—C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e),—OC(O)OR^(e), —OC(O)NR^(f)R^(g), —OC(═NR)NR^(f)R^(g), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g),—NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(f), —NR^(e)C(O)NR^(f)R^(g),—NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h),—NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e),—S(O)₂R^(e), —S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein eachR^(e), R^(f), R^(g), and R^(h) is independently (i) hydrogen ordeuterium; (ii) C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₁₀cycloalkyl, C₆-C₁₅ aryl, C₇-C₁₆ aralkyl, heteroaryl, or heterocyclyl; or(iii) R^(f) and R^(g) together with the N atom to which they areattached form heterocyclyl.

In other embodiments, the compound is a compound of Formula II:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In other embodiments, the compound of the invention has Formula VIII:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In other embodiments, the compound of the invention has Formula IX:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In other embodiments, the compound of the invention has Formula X:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In other embodiments, the compound of the invention has Formula XI:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In other embodiments, the compound of the invention has Formula XII:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In other embodiments, the compound of the invention has the followinggeneral Formula XIII:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In other embodiments, the compound of the invention has Formula XIV:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In other embodiments, the compound of the invention has Formula XV:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In other embodiments, the compound of the invention has Formula XVI:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In other embodiments, the compound of the invention has Formula XVIII:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In other embodiments, the compound of the invention has Formula XVIII:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In other embodiments, the compound of the invention has Formula XIX:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In other embodiments, the compound of the invention has Formula XX:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In other embodiments, the compound of the invention has Formula XXI:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In other embodiments, the compound of the invention has Formula XXII:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In some embodiments, Y is CR_(5a) or N. In other embodiments, Y isCR_(5a). In further embodiments, R_(5a) is H, deuterium, or halo. Inother embodiments, R_(5a) is H, deuterium, fluoro, or chloro. In otherembodiments, Y is N. In other embodiments, W is CR_(5a). In otherembodiments, R_(5a) is H or deuterium. In other embodiments, W is N. Inother embodiments, X is CR_(5a). In other embodiments, R_(5a) is H,deuterium, or amino. In other embodiments, X is N. In other embodiments,Z is CR_(5a). In other embodiments, R_(5a) is H or deuterium. In otherembodiments, Z is N. In some embodiments, Y is a bond. In someembodiments, W is CR_(5a). In some embodiments, R_(5a) is H ordeuterium. In some embodiments, W is NR_(5b). In some embodiments,R_(5b) is H or deuterium. In some embodiments, W is N. In someembodiments, W is O. In some embodiments, W is S. In some embodiments, Xis CR_(5a). In some embodiments, R_(5a) is H or deuterium. In someembodiments, X is NR_(5b). In some embodiments, R_(5b) is H ordeuterium. In some embodiments, X is N. In some embodiments, X is O. Insome embodiments, X is S. In some embodiments, Z is CR_(5a). In someembodiments, Z is NR_(5b). In some embodiments, Z is N. In someembodiments, Z is O. In some embodiments, Z is S. In other embodiments,R₁ is H, deuterium, C₁-C₈ alkyl optionally substituted with one or moresubstituents Q, C(O)R^(1a), or C(O)OR^(1a). In other embodiments, R₁ isH. In other embodiments, R₂ is H, deuterium, C₁-C₈ alkyl optionallysubstituted with one or more substituents Q, C(O)R^(1a), or C(O)OR^(1a).In other embodiments, R₂ is H. In other embodiments, R₃ is H. In otherembodiments, R₄ is H. In other embodiments, R₆ is H, deuterium, C₁-C₈alkyl, C₅-C₁₀ cycloalkyl, or heterocyclyl; wherein the alkyl,cycloalkyl, heterocyclyl are each independently and optionallysubstituted with one or more substitutes Q. In other embodiments, R₆ isC₁-C₈ alkyl, C₅-C₁₀ cycloalkyl, or 4-6 membered heterocyclyl; each ofwhich is independently and optionally substituted with one or moresubstitutes Q. In other embodiments, R₆ is C₁-C₈ alkyl, optionallysubstituted with one or more substitutes Q. In other embodiments, R₆ ismethyl. In other embodiments, R₇ is (i) H or deuterium; or (ii) C₁-C₈alkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl-C₁-C₈ alkyl, C₆-C₁₅ aryl,heteroaryl, or heterocyclyl, each of which is independently andoptionally substituted with one or more substitutes Q. In otherembodiments, R₇ is C₁-C₈ alkyl optionally substituted with one or moresubstitutes Q. In other embodiments, R₇ is C₁-C₈ alkyl substituted withone or more of C₃-C₇ cycloalkyl, C₆-C₁₅ aryl, heteroaryl, andheterocyclyl. In other embodiments, R₇ is C₃-C₇ cycloalkyl-C₁-C₈ alkyl.In other embodiments, R₇ is cyclopropylmethyl. In other embodiments, R₈is H.

In other embodiments, a compound of the invention is selected from:

and tautomers, mixtures of two or more tautomers, and isotopic variantsthereof; and pharmaceutically acceptable salts, solvates, hydrates, andprodrugs thereof.

Example 1: Synthesis of5-(cyclopropylmethyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1)

Step 1: Cyclopropyl(1-methyl-1H-pyrazol-5-yl)methanol (1-2): To asolution of compound N-methylpyrazole (1-1, 8.00 g, 97.44 mmol, 1.00 eq)in THF (160 mL) was added drop-wise n-BuLi (2.5 M, 46.77 mL, 1.20 eq) at−78° C. After 1 h at −78° C., a solution of cyclopropanecarbaldehyde(8.20 g, 116.93 mmol, 1.20 eq) in THF (80 mL) was added drop-wise. Theresulting mixture was stirred at 20° C. for 16 h, poured into aqueousNH₄Cl (300 mL) and stirred for 10 min. The aqueous phase was extractedwith ethyl acetate (100 mL×2). The combined organic phase was washedwith brine (100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by columnchromatography (SiO₂) to give compound 1-2 (12.00 g, 78.85 mmol, 80.9%yield, 100% purity) as a colorless oil. LCMS:RT=0.118 min, m/z 153.1[M+H]⁺.

Step 2: 5-(Cyclopropylmethyl)-1-methyl-1H-pyrazole (1-3): A mixture ofcompound 1-2 (9.00 g, 59.14 mmol, 1.00 eq), TFA (40.46 g, 354.84 mmol,26.27 mL, 6.00 eq) and Et₃SiH (41.26 g, 354.84 mmol, 56.52 mL, 6.00 eq)in DCM (900 mL) was stirred at 40° C. for 36 h. The mixture was adjustedto pH=8 with aqueous NaHCO₃ and separated. The organic layer wasconcentrated and purified by prep HPLC (basic condition) to givecompound 1-3 (2.10 g, 15.42 mmol, 26.1% yield) as a dark brown oil.LCMS:RT=0.565 min, m/z 137.1 [M+H]⁺.

Step 3: 4-Bromo-5-(cyclopropylmethyl)-1-methyl-1H-pyrazole (1-4): To asolution of compound 1-3 (2.10 g, 15.42 mmol, 1.00 eq) in DCM (21 mL)was added NBS (3.02 g, 16.96 mmol, 1.10 eq) at 0° C. The mixture wasstirred at 20° C. for 2 h, concentrated and purified by columnchromatography (SiO₂) to give compound 1-4 (3.00 g, 13.95 mmol, 90.5%yield) as a yellow oil. LCMS:RT=0.784 min, m/z 217.1 [M+H]⁺ ¹H NMR(CDCl₃, 400 MHz) δ 7.39 (s, 1H), 3.87 (s, 3H), 2.65-2.63 (d, J=8.8 Hz,2H), 0.98-0.94 (m, 1H), 0.55-0.51 (m, 2H), 0.29-0.25 (m, 2H).

Step 4:5-(Cyclopropylmethyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1): To a solution of compound 1-4 (3.00 g, 13.95 mmol, 1.00 eq) in THF(60 mL) was added n-BuLi (2 M, 10.46 mL, 1.50 eq) drop-wise at −78° C.After 30 min, a solution of2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.19 g, 27.90mmol, 2.00 eq) in THF (6 mL) was added. The resulting mixture was warmedto 20° C. and stirred for 0.5 h, diluted with saturated NH₄Cl (50 mL)and extracted with EA (100 mL). The organic layer was concentrated andpurified by column chromatography (SiO₂) to give compound 1 (3.30 g,11.40 mmol, 81.7% yield, 90.5% purity) as a colorless oil. LCMS:RT=0.801min, m/z 263.2 [M+H]⁺ ¹H NMR (CDCl₃, 400 MHz): δ 7.67 (s, 1H), 3.85 (s,3H), 2.82-2.81 (d, J=6.8 Hz, 2H), 1.30 (s, 12H), 0.92-0.90 (m, 1H),0.45-0.42 (m, 2H), 0.29-0.27 (m, 2H).

Example 2: Synthesis of(1r,4r)-N1-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexane-1,4-diamine(A104)

Step 1:2,5-Dichloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyridine(104-2): To a mixture of 2,5-dichloro-4-iodopyridine (104-1, 523.13 mg,1.91 mmol, 1.00 eq) and compound 1 (500.8 mg, 1.91 mmol, 1.0 eq) in DME(10 mL) were added Na₂CO₃ (2M, 2.87 mL, 3.00 eq) andBis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloro palladium(II) (67.62 mg, 95.50 μmol, 67.62 μL 0.05 eq). The resulting mixture wasstirred at 80° C. for 2 h under nitrogen, cooled to room temperature,concentrated and purified by column chromatography to give 104-2 (200mg, 659.3 μmol, 34.5% yield, 93.0% purity) as a yellow oil.LCMS:RT=0.825 min, m/z 282.0 [M+H]⁺.

Step 2:(1r,4r)-N1-(5-Chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexane-1,4-diamine(A104): To a mixture of 104-2 (180.00 mg, 637.91 μmol, 1.00 e q) and(1r,4r)-cyclohexane-1,4-diamine (145.69 mg, 1.28 mmol, 2.00 eq) indioxane (2.70 mL) was added t-BuONa (2M, 956.87 μL, 3.00 eq) andBis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)(32.69 mg, 63.79 μmol, 0.10 eq). The mixture was stirred at 90° C. for12 h under nitrogen, cooled to room temperature, filtered, concentratedand purified by prep-HPLC to give A104 (50 mg, 125.4 μmol, 19.7% yield,99.4% purity, HCl) as a white solid. LCMS:RT=2.309 min, m/z 360.1 [M+H]⁺¹H NMR (MeOD, 400 MHz): δ 8.07 (s, 1H), 7.83 (s, 1H), 7.06 (s, 1H), 3.99(s, 3H), 3.79-3.73 (m, 1H), 3.23-3.20 (m, 1H), 2.80-2.78 (d, J=6.8 Hz,1H), 2.22-2.14 (m, 4H), 1.68-1.55 (m, 4H), 0.93-0.90 (m, 1H), 0.51-0.47(m, 2H), 0.14-0.12 (m, 2H).

Example 3: Synthesis of(1r,4r)-N1-(6-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexane-1,4-diamine(A105)

Step 1:2-Chloro-6-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyridine(105-2): To a solution of 2,6-dichloropyridine (562 mg, 3.81 mmol, 1.00eq) and compound 1 (1.00 g, 3.81 mmol, 1.0 eq) in DME (20 mL) was addedNa₂CO₃ (2M, 5.72 mL, 3.00 eq) andBis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(134.89 mg, 190.5 umol, 134.89 uL, 0.05 eq). The mixture was stirred at80° C. for 2 h, cooled to room temperature, concentrated and purified bycolumn chromatography to give 105-2 (500 mg, 1.32 mmol, 34.6% yield,74.5% purity) as a yellow oil. LCMS:RT=0.835 min, m/z 248.1 [M+H]⁺.

Step 2:(1r,4r)-N1-(6-(5-(Cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexane-1,4-diamine(A105): To a solution of 105-2 (400.00 mg, 1.61 mmol, 1.00 eq) and(1r,4r)-cyclohexane-1,4-diamine (275.77 mg, 2.42 mmol, 1.50 eq) indioxane (8 mL) was added t-BuONa (2M, 2.42 mL, 3.00 eq) andBis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(82.50 mg, 161.00 μmol, 0.10 eq). The mixture was stirred at 90° C. for12 h, cooled to room temperature, and filtered. The filtrate wasconcentrated and purified by prep-HPLC to give A105 (120 mg, 331.25μmol, 20.6% yield, 99.9% purity, HCl) as a yellow solid. LCMS:RT=2.164min, m/z 326.2 [M+H]⁺ ¹HNMR (MeOD, 400 MHz): δ 8.01-7.97 (m, 2H),7.10-7.08 (d, J=9.2 Hz, 1H), 6.96-6.94 (d, J=7.2 Hz, 1H), 3.96 (s, 3H),3.79-3.77 (m, 1H), 3.22-3.17 (m, 1H), 2.92-2.91 (d, J=6.4 Hz, 1H),2.21-2.13 (m, 4H), 1.68-1.55 (m, 4H), 0.95-0.93 (m, 1H), 0.52-0.48 (m,2H), 0.18-0.16 (m, 2H).

Example 4: Synthesis of(1r,4r)-N1-(6-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)cyclohexane-1,4-diamine(A106)

Step 1:4-Chloro-6-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidine(106-2): To a solution of 4,6-dichloropyrimidine (284.5 mg, 1.91 mmol,1.00 eq) and compound 1 (500.0 mg, 1.91 mmol, 1.00 eq) in dioxane (10mL) was added Na₂CO₃ (2 M, 5.73 mL, 6.00 eq) and Pd(PPh₃)₄ (110.4 mg,95.5 umol, 0.05 eq). The mixture was stirred at 90° C. for 2 h undernitrogen, cooled to room temperature, concentrated and purified bycolumn chromatography to give 106-2 (200.00 mg, 562.9 μmol, 29.5% yield,70% purity) as a colorless oil. LCMS:RT=0.784 min, m/z 249.0 [M+H]⁺.

Step 2:(1r,4r)-N1-(6-(5-(Cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)cyclohexane-1,4-diamine(A106): To a solution of compound 106-2 (180.0 mg, 723.73 μmol, 1.00 eq)in BuOH (1.8 mL) were added (1r,4r)-cyclohexane-1,4-diamine (165.3 mg,1.45 mmol, 2.00 eq) and DIEA (374.1 mg, 505.59 μL 4.00 eq). The mixturewas stirred at 120° C. for 16 h, cooled to room temperature, andfiltered. The filtrate was concentrated and purified by prep-HPLC togive A106 (30.00 mg, 82.67 μmol, 11.4% yield, 100% purity, HCl) as ayellow solid. LCMS:RT=1.231 min, m/z 327.2 [M+H]⁺ ¹HNMR (MeOD, 400 MHz):δ 8.62 (s, 1H), 7.88 (s, 1H), 6.78 (s, 1H), 4.20-4.15 (m, 1H), 3.94 (s,3H), 3.21-3.17 (m, 1H), 2.20-2.14 (m, 4H), 1.61-1.53 (m, 4H), 1.02-1.00(m, 1H), 0.59-0.54 (m, 2H), 0.26-0.22 (m, 2H).

Example 5: Synthesis ofN4-((1r,4r)-4-aminocyclohexyl)-6-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine(A107)

Step 1:4-Chloro-6-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine(107-2): To a solution of 4,6-dichloropyrimidin-2-amine (313.22 mg, 1.91mmol, 1.00 eq) and compound 1 (500.00 mg, 1.91 mmol, 1.00 eq) in dioxane(1.0 mL) was added Na₂CO₃ (2M, 5.73 mL, 6.00 eq) and Pd(PPh₃)₄ (110.36mg, 95.50 μmol, 0.05 eq). The mixture was stirred at 90° C. for 2 hunder nitrogen, cooled to rt, concentrated and purified by columnchromatography to give 107-2 (220.00 mg, 458.8 μmol, 24.0% yield, 55%purity) as a yellow solid. LCMS:RT=0.724 min, m/z 264.0 [M+H]⁺.

Step 2:N4-((1r,4r)-4-Aminocyclohexyl)-6-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine(A107): To a solution of compound 5-2 (180.0 mg, 682.52 μmol, 1.00 eq)in BuOH (1.8 mL) were added (1r,4r)-cyclohexane-1,4-diamine (155.87 mg,1.37 mmol, 2.00 eq) and DIEA (352.84 mg, 476.80 μL 4.00 eq). The mixturewas stirred at 120° C. for 16 h, cooled to room temperature, andfiltered. The filtrate was concentrated and purified by prep-HPLC togive A107 (40.00 mg, 93.86 μmol, 13.7% yield, 97.2% purity, 2HCl) as ayellow solid. LCMS:RT=2.140 min, m/z 342.2 [M+H]⁺ ¹HNMR (MeOD, 400 MHz)δ 7.81 (s, 1H), 6.14 (s, 1H), 4.07-4.02 (m, 1H), 3.92 (s, 3H), 3.19-3.13(m, 1H), 2.92-2.90 (d, J=6.00 Hz, 2H), 2.19-2.12 (m, 4H), 1.60-1.45 (m,4H), 1.00-0.99 (m, 1H), 0.56-0.53 (m, 2H), 0.24-0.20 (m, 2H).

Example 6: Synthesis of2-(((1r,4r)-4-aminocyclohexyl)amino)-6-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ol(A108)

Step 1:4-Chloro-6-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine(11): To a solution of compound 1 (1.00 g, 3.81 mmol, 1.0 eq) in dioxane(20 mL) was added compound 10 (743 mg, 3.81 mmol, 1.0 eq), Pd(dppf)C₁₂(139.39 mg, 190 μmol, 0.05 eq), and Na₂CO₃ (2M, 3.81 mL, 2.0 eq) undernitrogen. The resulting mixture was stirred at 100° C. for 16 hrs undernitrogen. The mixture was filtered and the filtrate was concentrated andpurified by silica gel column (PE:EA=4:1, Rf=0.4) to give compound 11(600 mg, 1.49 mmol, 39% yield, 73% purity). LCMS:RT=0.894 min, m/z 295.0[M+H]⁺.

Step 2:4-(5-(Cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-6-((4-methoxybenzyl)oxy)-2-(methylthio)pyrimidine(12): To a solution of PMB-OH (327 mg, 2.36 mmol, 294 μL 1.2 eq) in DMF(6 mL) was added NaH (102 mg, 2.56 mmol, 60% purity, 1.3 eq) at 0° C.After stirred for 1 hr, compound 11 (580 mg, 1.97 mmol, 1.0 eq) in THF(1.50 mL) was added drop-wise at 0° C. The resulting mixture was stirredat 20° C. for 15 hrs. The reaction was quenched with aq. NH₄Cl (50 mL)and extracted with EA (50 mL×2). The organic layers were concentratedand purified by silica gel column (PE:EA=10:1-5:1) to give compound 12(140 mg, 236 μmol, 12% yield, 67% purity). LCMS:RT=0.984 min, m/z 397.0[M+H]⁺; ¹HNMIR (CDCl₃, 400 MHz) δ 7.81 (s, 1H), 7.40-7.38 (d, J=2.4 Hz,2H), 7.30 (m, 1H), 6.93-6.91 (m, 3H), 6.55 (s, 1H), 5.36 (s, 2H), 4.63(s, 1H), 3.88 (s, 3H), 3.82 (s, 5H), 3.19-3.18 (d, J=6.00 Hz, 2H), 2.60(s, 3H), 1.09-1.04 (m, 1H), 0.50-0.45 (m, 2H), 0.28-0.25 (m, 2H).

Step 3:4-(5-(Cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-6-((4-methoxybenzyl)oxy)-2-(methylsulfonyl)pyrimidine(13): To a solution of compound 12 (130 mg, 328 μmol, 1.0 eq) in DCM(2.6 mL) was added m-CPBA (177 mg, 820 μmol, 80% purity, 2.5 eq) at 0°C. The mixture was stirred at 15° C. for 2 hrs. The mixture was dilutedwith water (10 mL) and extracted with DCM (10 mL×2). The organic layerswere washed with aq. NaHCO₃ (10 mL). The organic layer was concentratedand purified by prep-TLC (PE:EA=1:1, Rf=0.4) to give compound 13 (80 mg,170 μmol, 52% yield, 91% purity). LCMS:RT=0.856 min, m/z 429.0 [M+H]⁺.

Step 4:(1r,4r)-M-(4-(5-(Cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)-6-((4-methoxybenzyl)oxy)pyrimidin-2-yl)cyclohexane-1,4-diamine(14): To a solution of compound 13 (80 mg, 187 μmol, 1.0 eq) in dioxane(1.2 mL) was added trans-cyclohexane-1,4-diamine (85 mg, 747 μmol, 4.0eq). The mixture was stirred at 120° C. for 2 hrs with microwave. Themixture was filtered and concentrated to give compound 14 (100 mg,crude), which was used directly for next step without furtherpurification. LCMS:RT=0.761 min, m/z 463.3 [M+H]⁺.

Step 5:24(1r,4r)-4-Aminocyclohexyl)amino)-6-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ol(A108): The mixture of compound 14 (100 mg, 216 μmol, 1.0 eq) in TFA (2mL) was stirred at 15° C. for 2 hrs. The mixture was concentrated andpurified by prep-HPLC to give compound A108 (20 mg, 57 μmol, 26% yield,98% purity). LCMS:RT=2.668 min, m/z 343.2 [M+H]⁺; ¹HNMR (CD₃OD, 400 MHz)δ 7.92 (s, 1H), 3.92 (s, 4H), 3.18-3.17 (m, 1H), 3.00 (s, 2H), 2.23-2.14(m, 4H), 1.59-1.55 (m, 4H), 1.03 (s, 1H), 0.58-0.53 (m, 2H), 0.27-0.23(m, 2H).

Example 7: Synthesis of(1r,4r)-N¹-(5-(5-(Cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)thiazol-2-yl)cyclohexane-1,4-diamine(A110)

Step 1: Tert-butyl (tert-butoxycarbonyl)-(5-bromothiazol-2-yl)carbamate(110-2): To a solution of tert-butyl (5-bromothiazol-2-yl)carbamate (0.5g, 1.79 mmol, 1.0 eq) in THF (20 mL) was added di-tert-butyl dicarbonate(0.39 g, 1.79 mmol, 1.0 eq) and DMAP (0.1 g, 0.9 mmol 0.5 eq). Theresulting mixture was stirred at 60° C. for 30 min, cooled to roomtemperature, diluted with H₂O (25 mL), and extracted with EtOAc (50mL×2). The combined organic layers were dried, filtered, concentrated,and purified by prep-TLC to give compound 110-2 (0.35 g, 0.92 mmol, 55%yield). LCMS:RT=0.944 min, m/z 379.0 [M+H]⁺; ¹HNMR (CDCl₃, 400 MHz) δ7.40 (s, 1H), 1.54 (s, 18H).

Step 2:N,N-Bis(tert-butoxycarbonyl)-5-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)thiazol-2-amine(110-3): To a solution of compound 110-2 (100 mg, 0.26 mmol, 1.0 eq) intoluene (10 mL) was added compound 1 (69 mg, 0.26 mmol, 1.0 eq) andK₂CO₃ (109 mg, 0.79 mmol, 3.0 eq) under N₂, followed by addition ofPd(PPh₃)₄ (3.5 mg, 2.64 μmmol, 0.01 eq) under N₂. The reaction washeated at 110° C. for 2 hrs and cooled to room temperature. The mixturewas poured into water (25 mL) and extracted with EtOAc (50 mL×2). Thecombined organic layers were washed with brine (10 mL), dried, filtered,concentrated, and purified by prep-TLC to give compound 110-3 (10 mg, 30μmol, 11% yield). LCMS:RT=0.922 min, m/z 435.3 [M+H]⁺; ¹HNMR (CDCl₃, 400MHz) δ 7.38 (m, 1H), 7.12 (m, 1H), 3.75 (s, 3H), 2.65-2.63 (m, 2H), 1.34(s, 18H), 0.82-0.80 (m, 1H), 0.37-0.35 (m, 2H), 0.03-0.00 (m, 2H).

Step 3:5-(5-(Cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)thiazol-2-amine(110-4): A mixture of compound 110-3 and HCl is stirred at roomtemperature for 1 hr and then concentrated to give compound 110-4.

Step 4: Tert-butyl(44(5-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)thiazol-2-yl)amino)cyclohexyl)carbamate(110-5): To a mixture of compound 110-4 (1.0 eq) and tert-butyl(4-oxocyclohexyl)carbamate (1.0 eq) in DCM are added AcOH (1.0 eq) andNaBH(OAc)₃ (2.0 eq). The resulting mixture is stirred at 20° C. for 2hrs, and then quenched with H₂O and worked up to give compound 110-5.

Step 5:N¹-(5-(5-(Cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)thiazol-2-yl)cyclohexane-1,4-diamine(110-6): To a solution of compound 108-5 (1.0 eq) in DCM is added TFA at0° C. The resulting mixture is stirred at 20° C. for 1 hr and thenworked up to give compound 110-6, which is further purified with HPLC togive compound A110.

Example 8: Dose-Response Compound Screen in RKO Cells

RKO colorectal cells were incubated with serial dilutions of each of thecompounds (at a concentration range of 0.167-1.5 μM or 0.11-1 μM inDMSO) for 16 hours at 37° C. Cells were washed with PBS and cell pelletswere incubated with ice cold protein lysis buffer containing proteaseinhibitor cocktail ( 1/200; Calbiochem) and phosphatase inhibitors (20mM p-nitrophenyl phosphate (PNPP), 20 mM β-glycerophosphate and 300 nMokadaic acid). Western blot (WB) analysis was performed by means ofstandard techniques. Blots were incubated with antibodies detectingβ-catenin ( 1/2,500; BD Transduction), p53 (DO-1&1801 hybridoma mix;dilution of 1:20 of supernatants from each), CKIα (C-19; 1/1,000; SantaCruz Biotechnology) and phospho-histone H2AX (S139; 1/1,000; Millipore).Secondary antibodies were HRP-linked goat anti-mouse, goat anti-rabbitand rabbit anti-goat antibodies (all 1/10,000; Jackson). Blots weredeveloped using ECL (GE Healthcare). Signal intensities corresponding toβ-catenin and p53 stabilization and phosphorylation of H2AX (γH2AX—amarker of DNA damage)-indicators of CKIα inhibition (Elyada et al.,Nature 1991), were analyzed by the ImageJ software. Relative signalintensities are depicted in Table 1 (see also in FIG. 1), where valuesof 1 correspond to signals of mock (DMSO)-treated cells.

TABLE 1 Activity of Compounds of the Invention Mass H2AX p53 β-CateninCmpd. Structure (M + H⁺) phosphorylation stabilization stabilizationA104

Calc'd for C₁₉H₂₇ClN₅: 360.2; Found 360.1 20 20 9 A105

Calc'd for C₁₉H₂₈N₅: 326.2; Found 326.2 1 2 5 A106

Calc'd for C₁₉H₂₇N₆: 327.2; Found: 327.2 1 1 9 A107

Calc'd for C₁₉H₂₈N₇: 342.2; Found: 342.2 1 2 4 A108

Calc'd for C₁₈H₂₇ClN₆O: 378.9; Found: 378.9 1 1 9 A102

Calc'd for C₂₂H₂₉Cl₂N₇: 462.42; Found: 462.42 1 1 4

The invention claimed is:
 1. A compound of Formula (I):

or a stereoisomer or a pharmaceutically acceptable salt thereof;wherein: R₁ and R₂ are each independently selected from H; and straightor branched C₁-C₈ alkyl, straight or branched C₁-C₅ alkoxy,—C(O)-(straight or branched C₁-C₅ alkyl), phenyl, naphthyl, anthracenyl,and C₃-C₇ heteroaryl, each optionally substituted by at least one ofhalide, hydroxyl, —C(O)OR₁₀, —OC(O)R₁₀, —R₁₃OR_(14′), —OR_(15′), phenyl,naphthyl, anthracenyl, C₃-C₇ heteroaryl, —C(O)NR₁₁R_(12′), and—NR₁₁C(O)R_(12′); or R₁ and R₂ together with the nitrogen atom they areconnected to form a 4-7 membered saturated, unsaturated, or aromaticring that optionally comprises at least one of N, O, NH, C═O, and SO₂,and is optionally substituted with at least one of straight or branchedC₁-C₅ alkyl, phenyl, naphthyl, anthracenyl, C₃-C₇ heteroaryl, hydroxyl,halide, and cyano; R₃ and R₄ are each independently selected from H, andstraight or branched C₁-C₈ alkyl optionally substituted by at least oneof halide, hydroxyl, C₁-C₅ alkoxy, phenyl, naphthyl, anthracenyl, C₃-C₇heteroaryl, —C(O)OR₁₀, —OC(O)R₁₀, —C(O)NR₁₁R_(12′), and—NR₁₁C(O)R_(12′); or R₁ or R₂ together with R₃ and the carbon andnitrogen atoms they are each connected to form a 4-7 membered saturated,unsaturated, or aromatic ring that optionally comprises includes atleast one of N, NH, O, C═O, and SO₂, and is optionally substituted withat least one of straight or branched C₁-C₅ alkyl, phenyl, naphthyl,anthracenyl, C₃-C₇ heteroaryl, hydroxyl, and halide; W, X, Y, and Z areeach independently selected from CH, CR₅, CR_(5c), NH, N, and S;provided that at least one of W, X, Y and Z is selected from NH, N, andS; and provided that, when W is N and Z is N, then X is CR_(5c); n is aninteger of 0 or 1; R₅ is selected from OH, NH₂, and halide; R₅, is OH orNH₂; R₈ is selected from H and halide; and straight or branched C₁-C₈alkyl, straight or branched C₂-C₈ alkenyl, and straight or branchedC₂-C₈ alkynyl, each optionally substituted by at least one halide; R₆ isselected from straight or branched C₁-C₈ alkyl, straight or branchedC₂-C₈ alkenyl, straight or branched C₂-C₈ alkynyl, C₅-C₁₀ cycloalkyl,and saturated or unsaturated 4-6 membered heterocyclyl, each optionallysubstituted by at least one of straight or branched C₁-C₈ alkyl, C₃-C₇cycloalkyl, 4-6 membered heterocyclyl, phenyl, naphthyl, anthracenyl,C₃-C₇ heteroaryl, halide, hydroxyl, and C₁-C₅ haloalkyl; R₇ is selectedfrom straight or branched C₁-C₈ alkyl, straight or branched C₂-C₈alkenyl, and straight or branched C₂-C₈ alkynyl, each independentlysubstituted by at least one of C₃-C₇ cycloalkyl, 4-6 memberedheterocyclyl, phenyl, naphthyl, anthracenyl, C₃-C₇ heteroaryl, halide,hydroxyl, and C₁-C₅ haloalkyl; each R₁₀ is independently straight orbranched C₁-C₈ alkyl; each R₁₁ and R_(12′) is independently H, orstraight or branched C₁-C₈ alkyl; each R₁₃ is independently straight orbranched C₁-C₈ alkylene; and each R₁₄′ and R₁₅′ is independently H, orstraight or branched C₁-C₈ alkyl; wherein each heteroaryl independentlycomprises at least one heteroatom selected from N, O, and S and eachheterocyclyl independently comprises at least one heteroatom selectedfrom N, O, and S.
 2. The compound according to claim 1, wherein R₁ andR₂ are each independently selected from H, and straight or branchedC₁-C₈ alkyl optionally substituted by at least one of halide, phenyl,naphthyl, anthracenyl, C₃-C₇ heteroaryl, hydroxyl, an ester, an ether,and an amide.
 3. The compound according to claim 1, wherein R₄ is H. 4.The compound according to claim 1, wherein R₃ and R₄ are each H.
 5. Thecompound according to claim 1, wherein R₅ is halide.
 6. The compoundaccording to claim 1, wherein R₅ is NH₂.
 7. The compound according toclaim 1, wherein R₅ is OH.
 8. The compound according to claim 1, whereinR₈ is selected from H, Cl, and straight or branched C₁-C₄ alkyl.
 9. Thecompound according to claim 1, wherein R₈ is H.
 10. The compoundaccording to claim 1, wherein at least one of R₁ and R₂ is H.
 11. Thecompound according to claim 1, wherein R₆ is selected from straight orbranched C₁-C₈ alkyl, C₅-C₁₀cycloalkyl, and saturated or unsaturated 4-6membered heterocyclyl; and R₇ is selected from straight or branchedC₁-C₈ alkyl, substituted by at least one of C₃-C₇ cycloalkyl, 4-6membered heterocyclyl, phenyl, naphthyl, anthracenyl, C₃-C₇ heteroaryl,halide, hydroxyl, and C₁-C₅ haloalkyl.
 12. The compound according toclaim 1, wherein R₆ is selected from straight or branched C₁-C₈ alkyl,C₅-C₁₀cycloalkyl, and 4-6 membered saturated heterocyclyl.
 13. Thecompound according to claim 1, wherein R₇ is straight or branched C₁-C₈alkyl substituted by at least one of C₃-C₇ cycloalkyl and hydroxyl. 14.The compound according to claim 1, wherein R₆ is straight or branchedC₁-C₈ alkyl, l each optionally substituted by at least one of straightor branched C₁-C₈ alkyl, C₃-C₇ cycloalkyl, halide, hydroxyl, and CF₃.15. The compound according to claim 1, wherein R₇ is straight orbranched C₁-C₈ alkyl substituted by at least one C₃-C₇ cycloalkyl. 16.The compound according to claim 1, wherein n is an integer of
 1. 17. Thecompound according to claim 1, wherein n is an integer of
 0. 18. Thecompound according to claim 1, wherein one of W, X, Y, and Z is N. 19.The compound according to claim 1, wherein two of W, X, Y, and Z is N.20. The compound according to claim 17, wherein two of W, X, Y, and Zare each independently selected from NH, N, and S.
 21. The compoundaccording to claim 1, selected from:

and stereoisomers and pharmaceutically acceptable salts thereof.
 22. Acompound selected from:


23. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound, or a stereoisomer or a pharmaceutically acceptablesalt thereof according to claim 1; and a pharmaceutically acceptableexcipient.
 24. A compound of Formula (IA):

or a stereoisomer or a pharmaceutically acceptable salt thereof;wherein: R₁ and R₂ are each independently selected from H; and straightor branched C₁-C₈ alkyl, straight or branched C₁-C₅ alkoxy,—C(O)-(straight or branched C₁-C₅ alkyl), phenyl, naphthyl, anthracenyl,and C₃-C₇ heteroaryl, each optionally substituted by at least one ofhalide, hydroxyl, —C(O)OR₁₀, —OC(O)R₁₀, —R₁₃OR_(14′), —OR_(15′), phenyl,naphthyl, anthracenyl, C₃-C₇ heteroaryl, —C(O)NR₁₁R_(12′), and—NR₁₁C(O)R_(12′); or R₁ and R₂ together with the nitrogen atom they areconnected to form a 4-7 membered saturated, unsaturated, or aromaticring that optionally comprises at least one of N, O, NH, C═O, and SO₂,and is optionally substituted with at least one of straight or branchedC₁-C₅ alkyl, phenyl, naphthyl, anthracenyl, C₃-C₇ heteroaryl, hydroxyl,halide, and cyano; R₃ and R₄ are each independently selected from H, andstraight or branched C₁-C₈ alkyl optionally substituted by at least oneof halide, hydroxyl, alkoxy, phenyl, naphthyl, anthracenyl, C₃-C₇heteroaryl, —C(O)OR₁₀, —OC(O)R₁₀, —C(O)NR₁₁R_(12′), and—NR₁₁C(O)R_(12′); or R₁ or R₂ together with R₃ and the carbon andnitrogen atoms they are each connected to form a 4-7 membered saturated,unsaturated, or aromatic ring that optionally comprises at least one ofN, NH, O, C═O, and SO₂, and is optionally substituted with at least oneof straight or branched C₁-C₅ alkyl, phenyl, naphthyl, anthracenyl,C₃-C₇ heteroaryl, hydroxyl, and halide; W, X, Y, and Z are eachindependently selected from CH, CR₅, NH, N, and S; provided that atleast one of W, X, Y and Z is selected from NH, N and S; provided that,when W is N and Z is N, then R₈ is other than H; n is an integer of 0 or1; R₅ is selected from OH, NH₂, and halide; R₈ is selected from H andhalide; and straight or branched C₁-C₈ alkyl, straight or branched C₂-C₈alkenyl, and straight or branched C₂-C₈ alkynyl, each optionallysubstituted by at least one halide; R₆ is selected from straight orbranched C₁-C₈ alkyl, straight or branched C₂-C₈ alkenyl, straight orbranched C₂-C₈ alkynyl, C₅-C₁₀ cycloalkyl, and saturated or unsaturated4-6 membered heterocyclyl, each optionally substituted by at least oneof straight or branched C₁-C₈ alkyl, C₃-C₇ cycloalkyl, 4-6 memberedheterocyclyl, phenyl, naphthyl, anthracenyl, C₃-C₇ heteroaryl, halide,hydroxyl, and C₁-C₅ haloalkyl; R₇ is selected from straight or branchedC₁-C₈ alkyl, straight or branched C₂-C₈ alkenyl, and straight orbranched C₂-C₈ alkynyl, each independently substituted by at least oneof C₃-C₇ cycloalkyl, 4-6 membered heterocyclyl, phenyl, naphthyl,anthracenyl, C₃-C₇ heteroaryl, halide, hydroxyl, and C₁-C₅ haloalkyl;each R₁₀ is independently straight or branched C₁-C₈ alkyl; each R₁₁ andR_(12′) is independently H, or straight or branched C₁-C₈ alkyl; eachR₁₃ is independently straight or branched C₁-C₈ alkylene; and eachR_(14′) and R_(15′) is independently H, or straight or branched C₁-C₈alkyl; wherein each heteroaryl independently comprises at least oneheteroatom selected from N, O, and S and each heterocyclyl independentlycomprises at least one heteroatom selected from N, O, and S.
 25. Acompound selected from:(1r,4r)-N¹-(5-chloro-4-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexane-1,4-diamine;(1r,4r)-N¹-(6-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)cyclohexane-1,4-diamine;(1r,4r)-N¹-(6-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)cyclohexane-1,4-diamine;N⁴-((1r,4r)-4-aminocyclohexyl)-6-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine;2-(((1r,4r)-4-aminocyclohexyl)amino)-6-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidin-4-ol;N²-((1r,4r)-4-aminocyclohexyl)-6-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)pyrimidine-2,4-diamine;and(1r,4r)-N¹-(5-(5-(cyclopropylmethyl)-1-methyl-1H-pyrazol-4-yl)thiazol-2-yl)cyclohexane-1,4-diamine;and stereoisomers and pharmaceutically acceptable salts thereof.